Abstract

4489

Background. The objective of this study is to improve the efficacy of photodynamic therapy (PDT) for the treatment of breast cancer. The procedure involves targeting a photosensitive dye to the receptor tissue factor (TF), which is expressed on many types of cancer cells and endothelial cells lining the inner surface of blood vessels in invasive tumors, including breast tumors, but not in normal tissue, thus providing a specific and accessible target for delivering a photosensitive dye to tumor cells and tumor blood vessels. The dye is targeted to TF by attaching factor VII, the natural ligand that binds to TF with exceptional affinity and specificity. Experimental procedures. We synthesized a factor VII molecule containing a peptide for chemically conjugating either Verteporfin or Sn(IV) chlorin e6 (SnCe6) dyes. The efficacy of the conjugated dye for PDT was tested in vitro and in vivo. The in vitro tests involved cell survival (viability assays), apoptosis (Caspase 3/7 assay) or necrosis (Cytotox assay) with mouse and human breast tumor cells, and with normal human 293 or unstimulated vascular endothelial cells as a control that does not express TF. The in vivo tests involved injecting the conjugated dye intravenously followed by irradiation of tumor with 689 nm (for Verteporfin) or 635nm laser (for SnCe6) in mice carrying a mouse or human breast tumor xenograft. Results. (1) Targeted Verteporfin or SnCe6 dyes showed a stronger PDT effect than the non-targeted dyes against mouse and human breast tumor lines in vitro and in vivo. (2) Non-targeted dyes, but not targeted dyes, showed a PDT effect against normal cells that do not express TF. Conclusions: Conjugating the photosensitive dyes Verteporfin and SnCe6 to factor VII for targeting the dyes to TF improved the efficacy and safety of PDT against mouse and human breast tumor cells in vitro and in vivo. Acknowledgements: The project was supported in part by the Yale Cancer Center/Swebilius Translational Cancer Research Award (ZH) and the Susan G. Komen Award from the Susan G. Komen for the Cure Foundation (ZH).